L. Jay Katz
BASICS
DESCRIPTION
Neuroprotection is the use of therapeutic agents to prevent, retard, and in some instances, reverse retinal ganglion cells (RGCs) death in glaucomatous patients.
PATHOPHYSIOLOGY
IOP dependent RGCs loss
• Elevated IOP induces optic neuropathy by:
– Mechanical theory, posterior bowing of lamina cribrosa, and damaging axon bundles passing through its pores
– Vascular theory, low perfusion pressure, defined as the difference between systemic blood pressure and IOP
• IOP is no longer regarded as the only causative factor in glaucomatous optic neuropathy because some patients with elevated IOP never develop glaucoma, in normal tension, glaucoma IOP is within normal limit, and some patients continue to progress with controlled low IOP.
Non-IOP dependent RGCs loss
• Excitotoxicity
– RGCs die by apoptosis (programmed cell death) because of the presence of excessive amounts of glutamate, an excitatory neurotransmitter.
– Glutamates binds onto postsynaptic receptors, NMDA (N-methyl-d-aspartate) channels, and keeps them open for a long period of time, thereby allowing influx of Ca2+ and Na+ ions and initiating apoptosis.
• Mitochondrial dysfunction
– Induced by glaucoma-related stimuli such as tumor necrosis factor and hypoxia
• Oxidative stress
– Load of reactive oxygen species and lipid peroxides outweigh the antioxidant capacity of cells
• Inflammatory and autoimmune mechanisms
– Complement system: Several components are upregulated.
– Heat shock proteins
– Under physiological conditions act as molecular chaperones and/or have anti-apoptotic activities.
– Glaucomatous patients have antibodies against HSP.
– TNF, as a mediator of RGC death is upregulated.
– Nitric oxide: It is a gaseous second messenger and appears to have physiologic role in optic nerve function. Excessive production of nitric oxide in glaucoma leads to RGCs loss.
DIAGNOSIS
DIAGNOSTIC TESTS & INTERPRETATION
Imaging
• Establishing neuroprotective effect of drugs is difficult because glaucoma is a slow, progressive disease and the current method of measuring progression, a computerized visual field assessment, is highly variable.
• Optic nerve and nerve fiber layer analyzers (Optical Coherent Tomography, Scanning Laser Polarimetry, and Ophthalmoscopy) may lead to more meaningful assessment.
• Detection of apoptosing retinal cells (DARC), an in vivo method, may become a precise tool to assess the effect of neuroprotective agents.
TREATMENT
MEDICATION
• To be deemed a neuroprotective agent should have 4 criteria: (1) Possessing receptors on the optic nerve or retina, (2) Adequate penetration into the vitreous and retina at pharmacologic levels, (3) Triggering intracellular signals that enhance neuronal resistance to apoptosis (4) Demonstration of efficacy in clinical trials.
• No neuroprotectant drug has ever been approved for an optic nerve disorder. Despite successful preclinical cell culture and animal model experiments, most of the phase 2 and virtually all of the phase 3 clinical trials of more than 100 neuroprotective drug candidates have failed to demonstrate efficacy and safety. Following are some of neuroprotectants that are categorized into 2 groups. Promoters of cell survival and inhibitors of cell death.
• Inhibitors of cell death
– Memantine, a derivative of amantadine, which was used as an anti-influenza compound. As a NMDA receptor antagonist, is currently the only available clinical glutamate modifier (the first phase 3 trial did not confirm a neuroprotective effect).
– Nitric oxide synthase inhibitors: Had a neuroprotective effect in animal studies.
– Infrared light, has metabolism-enhancing, antioxidant, and anti-apoptotic properties. A phase 0 clinical trial is currently announced to be in preparation.
– Vitamin E, scavenger of peroxyl radicals: Glaucoma patients receiving vitamin E have displayed improved visual fields in some studies.
– Calcium channel blockers: In addition to anti-vasospastic effect, that is an important mechanism in optic nerve damage in some glaucoma patients (i.e., normal tension glaucoma), its topical form may reduce IOP.
• Promoters of neuronal survival
– Brimonidine (α-2 agonist): Its mechanism of action is similar to an NMDA channel blocker, MK-801. It also causes upregulation of BDNF (brain-derived neurotrophic factor) in the RGCs. Neuroprotective effect in experimental studies, but in clinical trials failed to translate into similar efficacy in humans.
– Betaxolol (β1-blocker): Alters excitotoxic/hypoxic pathway to exert its neuroprotective effect. No definite clinical proof for having neuroprotective effect.
– Extract Ginkgo biloba, an extract from leaves of Ginkgo biloba, has been effective in models of experimental glaucoma.
– Neurotrophins, Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), have been tested extensively in animal studies, both reduce RGCs death. They activate toxic pathways as well as neuroprotective ones.
– Geranylgeraylacetone, in animal studies, upregulated HSP-72 expression in RGCs and protected them from glaucomatous damage.
– Cop-1 (glatiramer acetate; copolymer-1; copax-1): FDA approved drug for multiple sclerosis. In animal studies, Cop-1 reduced optic nerve damage caused by mechanical injury or intravitreal glutamate injection.
– Coenzyme Q10, plays a crucial role in energy production by the mitochondrial electron transport chain. Topical CoQ10 has been effective in experimental glaucoma.
ADDITIONAL READING
• Bessero AC, Clarke PG. Neuroprotection for optic nerve disorders. Curr Opin Neurol 2010;23:10–15.
• Sena DF, Ramchand K, Lindsley K. Neuroprotection for treatment of glaucoma in adults. Cochrane Database Syst Rev 2010;2:CD006539.
• Cheung W, Guo L, Cordeiro MF. Neuroprotection in glaucoma: Drug-based approaches. Optom Vis Sci 2008;85:406–416
CODES
ICD9
• 365.9 Unspecified glaucoma
• 365.12 Low tension open-angle glaucoma
CLINICAL PEARLS
• No evidence that neuroprotective agents are effective in preventing retinal ganglion cell death, and thus preserving vision in patients with glaucoma has been demonstrated. Long-term randomized clinical trials with long-term follow-up are needed to determine if they may be beneficial in this regard.
• Memantine is the only neuroprotective agent assessed in randomized clinical trials (phase 3) without showing a neuroprotective effect compared to placebo-treated patients.
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